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Food Chem Toxicol. 2002 Aug;40(8):1063-8.

Heterologous expression of human N-acetyltransferases 1 and 2 and sulfotransferase 1A1 in Salmonella typhimurium for mutagenicity testing of heterocyclic amines.

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  • 1German Institute of Human Nutrition, Department of Toxicology, Arthur-Scheunert-Allee 114-116, D-14558 Bergholz-Rehbr├╝cke, Germany. muckel@www.dife.de

Abstract

A variety of carcinogenic heterocylic amines (HAs) are found in cooked food. They can be metabolised to reactive intermediates via N-hydroxylation catalysed by cytochrome P450 1A2, followed by conjugation of the resulting N-hydroxyl group by N-acetyltransferase (NAT) or sulfotransferase (SULT). In order to compare the role of O-acetylation and O-sulfonation by human enzymes in the activation of HAs, we have introduced the cDNAs for wild-type forms of human NAT1, NAT2 and SULT1A1 in the acetyltransferase-deficient Salmonella typhimurium strain TA1538/1,8-DNP. Functional expression of recombinant proteins was demonstrated using immunoblot analysis and determination of enzyme activity with characteristic substrates. The established strains were used to study the mutagenicity of the N-hydroxy derivatives of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). The results demonstrate that N-hydroxy-HAs are activated by different human enzymes. At the concentrations used in the mutagenicity assay, N-hydroxy-IQ was activated by human NAT2, but not by NAT1 or SULT1A1. In contrast, N-hydroxy-PhIP was activated specifically by human SULT1A1, but not by NAT1 or NAT2. Therefore, both O-acetylation and O-sulfonation by human enzymes have to be regarded as important determinants for HA genotoxicity in humans.

PMID:
12067565
[PubMed - indexed for MEDLINE]
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